Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

How stable is perceived direction of gravity over extended periods in darkness?

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p < 0.05) increased errors in perceived direction of gravity by block 2 (SVV) and 3 (SVH). These increases disappeared after turning on the lights before block 7. Focusing on blocks 2-6, significant drift started from similar offset positions and pointed to the same direction in a majority of runs in 9/15 (SVV) and 11/15 (SVH) subjects. When pooling data from all blocks, orthogonality of errors was lost in all subjects. Trial-to-trial variability remained stable over the seven runs for SVV and SVH. Only when pooling all runs, precision was significantly (p < 0.05) higher for the SVH. Our findings suggest that perceived direction of gravity continues to fluctuate over extended recording periods with individuals showing unique patterns of direction-specific drift while variability remains stable. As subjects were upright during the entire experiment and as drift persisted over several blocks, sensory adaptation seems unlikely. We therefore favor a central origin of this kind of drift.

Temporal constancy of perceived direction of gravity assessed by visual line adjustments.

Here we investigated how well internal estimates of direction of gravity are preserved over time and if the subjective visual vertical (SVV) and horizontal (SVH) can be used inter-changeably. Fourteen human subjects repetitively aligned a luminous line to SVV, SVH or subjective visual oblique (± 45°) over 5 min in otherwise complete darkness and also in dim light. Both accuracy (i.e., the degree of veracity as reflected by the median adjustment error) and precision (i.e., the degree of reproducability as reflected by the trial-to-trial variability) of adjustments along the principle axes were significantly higher than along the oblique axes. Orthogonality was only preserved in a minority of subjects. Adjustments were significantly different between SVV vs. SVH (7/14 subjects) and between ±45° vs. -45° (12/14) in darkness and in 6/14 and 14/14 subjects, respectively, in dim light. In darkness, significant drifts over 5min were observed in a majority of trials (33/56). Both accuracy and precision were higher if more time was taken to make the adjustment. These results introduce important caveats when interpreting studies related to graviception. The test re-test reliability of SVV and SVH can be influenced by drift of the internal estimate of gravity. Based on spectral density analysis we found a noise pattern consistent with 1/fß noise, indicating that at least part of the trial-to-trial dynamics observed in our experiments is due to the dependence of the serial adjustments over time. Furthermore, using results from the SVV and SVH inter-changeably may be misleading as many subjects do not show orthogonality. The poor fidelity of perceived ± 45° indicates that the brain has limited ability to estimate oblique angles.

Persistent cardioprotection by azapropazone in a canine model of coronary artery thrombosis and thrombolysis.

Activated neutrophils and possibly xanthine oxidase-derived free radicals are believed to be mediators of ischemia and reperfusion-induced myocardial damage. We studied the cardioprotective effect of the neutrophil stabilizer and xanthine oxidase inhibitor azapropazone in dogs subjected to thrombotic occlusion of the left anterior descending coronary artery (LAD), induced by intracoronary introduction of a copper coil, followed 60 min later by thrombolytic treatment with intracoronary streptokinase and 4-day reperfusion; we then determined infarct size by triphenyltetrazolium stain. Azapropazone [100 mg/kg intravenously (i.v.) followed by a 24-h i.v. infusion of 10 mg/kg/h, n = 8] or vehicle (n = 10) treatments were started immediately before the streptokinase infusion. Steady-state plasma levels of azapropazone ranged from 97 to 163 micrograms/ml during the infusion. Myocardial blood flow and underperfused area at risk were determined using radiolabeled microspheres. Results were as follows (mean +/- SEM): area at risk (percentage of left ventricle) azapropazone 22.7 +/- 3.16 and vehicle 21.8 +/- 4.13; infarct size (percentage of area at risk), azapropazone 45.1 +/- 11.8 and vehicle 75.7 +/- 10.6, p less than 0.03; collateral blood flow (ml/min/g), azapropazone 0.27 +/- 0.02 and vehicle 0.23 +/- 0.02; total ischemic period (min), azapropazone 106 +/- 5.9 and vehicle 91.5 +/- 4.9. Azapropazone had no effects on heart rate (HR), blood pressure (BP), or rate/pressure product (RPP). These dta show that azapropazone limits infarct size in a canine model of coronary thrombosis and long-term reperfusion and that this cardioprotection is independent of cardiovascular parameters.